Correlation of CT features of lung adenocarcinoma with sex and age

This study aimed to retrospectively examine the computed tomography (CT) features of lung adenocarcinoma across different demographic groups. Preoperative chest CT findings from 1266 surgically resected lung adenocarcinoma cases were retrospectively analyzed. Lung adenocarcinomas were categorized based on CT characteristics into pure ground glass (pGGO), nodule-containing ground glass opacity (mGGO), and pure solid without containing ground glass opacity (pSD). These categories were correlated with sex, age, EGFR status, and five histopathological subtypes. The diameters of pGGO, mGGO, and pSD significantly increased across all patient groups (P < 0.05). Males exhibited a significantly higher proportion of pSD than females (P = 0.002). The mean diameters of pGGO and pSD were significantly larger in males than in females (P = 0.0017 and P = 0.043, respectively). The frequency of pGGO was higher in the younger age group (≤ 60 years) compared to the older group (> 60 years) for both males (P = 0.002) and females (P = 0.027). The frequency of pSD was higher in the older age group for both sexes. A linear correlation between age and diameter was observed in the entire cohort as well as in the male and female groups (P < 0.0001 for all groups). EGFR mutations were less frequent in pSD compared to pGGO (P = 0.0002) and mGGO (P < 0.0001). The frequency of lesions containing micropapillary components increased from pGGO to mGGO and pSD (P < 0.0001 for all). The frequency of lesions containing solid components also increased from pGGO to mGGO and pSD (P = 0.045, P < 0.0001, and P < 0.0001, respectively). The CT features of lung adenocarcinoma exhibit differences across genders and age groups. Male gender and older age are risk factors for lung adenocarcinoma growth.

Lung cancer is the leading cause of cancer-related death worldwide 1 .It is divided into small-cell lung cancer and non-small-cell lung cancer (NSCLC).NSCLC accounts for 85% of all lung cancers, with adenocarcinoma being the most common histological subtype, comprising 40% of all NSCLC cases 2 .Advancements in molecular biology have significantly improved the prognosis of NSCLC for patients with druggable mutations in the epidermal growth factor receptor (EGFR) or immune checkpoints PD-L1/PD1 3 .The advent of molecular targeted therapy has achieved significant success [4][5][6][7] .At the same time, it is essential to understand lung cancer to broaden our perspective comprehensively.Pulmonary nodules with ground-glass opacity (GGO), defined as hazy lesions on high-resolution CT that do not obscure bronchial structures or pulmonary vessels 8 , have been increasingly observed.This increase is attributable to the growing use of CT in lung cancer screening 9 and the increased availability of CT technology 10 , leading to a major concern due to increased detection rates 11 .
Persistent pulmonary GGOs are closely associated with lung adenocarcinoma 12 , and various types of GGO in lung adenocarcinoma are associated with different prognoses 13 .The formation of different GGOs has been correlated with factors such as age, sex, smoking habits, and EGFR status 10,[14][15][16] .Previous studies primarily focused on prospective follow-up scenarios.This study aims to examine the influence of sex and age on GGO growth from a clinical perspective.

Inclusion and exclusion criteria
The inclusion criteria for the study were patients who (a) underwent surgical resection and (b) were pathologically diagnosed with lung adenocarcinoma.A total of 734 patients were excluded for the following reasons: (a) unavailability of preoperative CT images (n = 56), (b) presence of multiple lesions (n = 350), (c) manifestation of diffuse miliary nodules in both lungs (n = 23), (d) obscuration of lesions by atelectasis, pneumonia, or massive pleural effusion (n = 34), (e) lack of detailed smoking history (n = 113).Additionally, 158 patients with a smoking history were excluded (156 males and 2 females).Therefore, 1266 patients, all of whom were Asian, were included in this study.

Patients' general characteristics
Medical records were reviewed to obtain information on sex, age, and smoking history.

Computed tomographic assessment
Preoperative chest CTs were performed using three scanners: GE Discovery CT750 HD, 64-slice LightSpeed VCT (GE Medical Systems), and somatom definition flash.The scanning parameters were set at 120 kVp, 100-200 mAs, with a pitch of 0.75-1.5 and collimation of 1-1.25 mm.All imaging data were reconstructed using a medium sharp reconstruction algorithm, with a slice thickness of 1-1.25 mm.

Computed tomographic image interpretation
The CT images were independently interpreted by a clinical radiologist with 35 years of experience (H.Q.L) and two other radiologists, each with 10 years of experience (F.L and E.N.W), on a retrospective basis.The radiologists were blinded to clinical and smoking status.The majority class was used as the final CT feature value.CT images were interpreted using both mediastinal (width = 350 HU; level = 40 HU) and lung (width = 1500 HU; level = −650 HU) window settings.Images were evaluated for lesion size, nodule types, and the presence of single or multiple lesions in both lungs.
Lesion classification was based on ground-glass opacity presence: lesions exhibiting only ground-glass opacity were classified as pure ground-glass opacity (pGGO).Lesions with > 50% but < 100% ground-glass opacity were classified as ground-glass opacity predominant lesions (mGGO).Those with > 1% but ≤ 50% ground glass opacity were classified as solid predominant lesions (mSD).Lesions without ground glass opacity were classified as pure solid lesions (pSD).For statistical purposes, mGGO and mSD were combined and classified as mGGO, resulting in three categories: pGGO, mGGO, and pSD.

EGFR mutation status analysis
The mutation status of EGFR exon 18-21 was determined using a polymerase chain reaction-based amplified refractory mutation system (ARMS) with a human EGFR gene mutation fluorescence polymerase chain reaction diagnostic kit (AmoyDx, China) from histology specimens of lung cancer patients.

Statistical analysis
Statistical analysis was conducted using SAS 9.4 (SAS Institute Inc, Cary, NC).The χ2 test was employed to evaluate differences in the distribution of categorical variables, while an independent t-test was used for continuous variables.Differences were considered statistically significant at P < 0.05.A linear correlation was performed between age and tumor diameter in different groups.

The frequency of pGGO, mGGO, and pSD in all populations and different sexes, as well as the diameter of each type of nodule
The diameters of pGGO, mGGO, and pSD consistently increased across all patients, reaching statistical significance (P < 0.05) (Table 1).There was no significant difference in the frequency of pGGO between males and females.However, the frequency of pSD was lower in females compared to males (P = 0.0002), and the frequencies of mGGO were significantly higher in females than in males (P = 0.002) (Table 2).The mean diameters of pGGO and pSD were significantly larger in males than in females (P = 0.0017 and P = 0.043, respectively) (Table 3).The constitute of different nodules between ≤ 60 and > 60 in male and female and mean diameter in different group pGGO was more frequent in the ≤ 60 years group than in the > 60 years group in both male and female (P = 0.002 and P = 0.026, respectively).Conversely, pSD was more frequent in the > 60 years group, with this difference reaching statistical significance in males and a marginal significance in females (P = 0.0138 and P = 0.053) (Table 4).The mean diameter of pGGO in patients aged > 60 years was larger than in those aged ≤ 60 years for both sexes, with statistical significance (P = 0.0116 for males and P = 0.0193 for females) (Table 5).The mean diameters of mGGO and pSD were larger in patients aged > 60 years than in those aged ≤ 60 years for both sexes.Specifically, in males, the diameter of mGGO reached statistical significance (P = 0.0357), while in females, it was marginally significant (P = 0.0745) (Table 6).However, differences in pSD diameters did not reach statistical significance (Table 7).Linear correlation analyses were performed between age and diameter across the whole group and within male and female subgroups.These analyses showed a linear correlation in all groups (R = 0.189 for the whole group, 0.187 for males, and 0.185 for females, respectively, P < 0.0001 for all three groups) (Table 8).www.nature.com/scientificreports/

Discussion
Some pGGOs progressively transform into pSDs 18,19 .Studies indicate that a GGO nodule initially increases in size, followed by the appearance and subsequent enlargement of a solid portion within the lesion 20 .Lesions transitioning from pGGO to mGGO or from mGGO to solid exhibit rapid size increases 10,21,22 .The volume doubling time (VDT) for pGGOs is approximately 600 to 900 days; for part-solid GGOs, it ranges from 300 to 450 days 23 ; and for solid nodules, it is about 149 days 24 .
The diameters of pGGO, mGGO, and pSD consistently increased, all reaching statistical significance, which aligns with previous findings.Mets OM et al. also observed that part-solid lesions are larger than pGGOs 25 .Further analysis showed that from pGGO to mGGO and pSD, the frequency of lesions containing micropapillary or solid histopathological subtypes significantly increased.Micropapillary and solid subtypes are highly invasive and associated with poor prognosis in lung adenocarcinoma 26 , explaining the gradual increase in lesion diameters from pGGO to mGGO and pSD.The analysis of EGFR status among pGGO, mGGO, and pSD revealed that the frequency of EGFR wild type was significantly higher in pSD than in pGGO and mGGO, consistent with previous studies 27 .
Previous research has identified male sex as an independent risk factor for GGO growth 14 .In this study, the frequency of pSD was higher and mGGO lower in males compared to females.The transition rate from pGGO through mGGO to pSD appears to be faster in males.Additionally, the mean diameters of pGGO, mGGO, and pSD were larger in males than in females, although the difference in mGGO did not reach statistical significance.These findings suggest a faster growth rate of GGOs in males.
Older age has also been identified as a risk factor for GGO growth 10,25,28 .Using 60 years as the cutoff point, our findings revealed that pGGO was less frequent and pSD more frequent in the > 60 age group, regardless of sex.The rapid growth of pSD compared to pGGO aligns with previous findings.Sui Q et al. analyzed 7605 patients with adenocarcinoma from the SEER (Surveillance, Epidemiology, and End Results) database and concluded that female sex and age ≤ 60 years are independent prognostic factors for better survival, supporting these findings 29 .These results were also confirmed by a larger study involving 61,928 patients conducted by Wu Y et al. 30 .
Furthermore, the diameters of different types of nodules across two age groups were compared.The diameters of pGGO and mGGO in the > 60 group were larger than in the ≤ 60 group (P < 0.05), except for the mGGO group in females, where the difference did not reach statistical significance (P = 0.0745).For pSD, there was no statistically significant difference in diameter between the two age groups for both sexes.A linear correlation analysis between age and nodule diameter for all groups (P < 0.0001 for all) further supports the conclusion that older age is a risk factor for tumor growth.
This study compared risk factors in sex and different ages for lung adenocarcinoma, excluding patients with a smoking history, which might reflect differences under natural conditions and provide a reference for future research.This study further affirms that lung adenocarcinoma is highly personalized [31][32][33] .In the future, a precise model for evaluating lung adenocarcinoma is needed.
In conclusion, being male and older age are risk factors for GGO growth.However, this study had several limitations: (1) The pathology of the disease was not included, and lung adenocarcinoma progression was evaluated (2) Due to its retrospective nature, it was not possible to calculate the VDT of GGO nodules; instead, diameter and GGO types were used as alternatives.
(3) The assessment of GGO proportions was based on visual evaluations without quantitative analysis of CT values.(4) This study did not distinguish whether patients were seen symptomatically or discovered during a physical examination.Future studies will address these aspects.

Table 1 .
Comparison of diameter for different nodules.Data for diameter are mean ± standard deviation (cm).Length unit = cm.pGGO pure ground glass opacity nodules, mGGO nodules containing GGO, pSD pure solid nodules without GGO.The P value was from the diameter of the same row versus the first row.

Table 2 .
Constitute of pGGO, mGGO, and pSD in male and female.Numbers in parentheses are percentages of the same group.pGGO pure ground glass opacity nodules, mGGO nodules containing GGO, pSD pure solid nodule.P values were from pGGO, mGGO, or pSD compared to other types.

Table 3 .
The diameter comparison of different groups of nodules between male and female.Data for diameter are mean ± standard deviation (cm).Length unit = cm.pGGO pure ground glass opacity nodules, mGGO nodules containing GGO, pSD pure solid nodules without GGO.

Table 5 .
The diameter comparison of pGGO between ≤ 60 and > 60 in male and female.Data for diameter are mean ± standard deviation (cm).Length unit = cm.pGGO pure ground-glass opacity nodules.

Table 6 .
The diameter comparison of mGGO between ≤ 60 and > 60 in male and female.Data for diameter are mean ± standard deviation (cm).Length unit = cm.mGGO nodules containing GGO.

Table 7 .
diameter of pSD of ≤ 60 and > 60 in male and female.Data for diameter are mean ± standard deviation (cm).Length unit = cm.pSD pure solid nodule without GGO.

Table 8 .
Linear correlation between age and diameter of lung adenocarcinoma.R = correlation coefficient.
n Range